Early in the history of vaccine development, it was discovered that addition of foreign substances, including particulate matter, to vaccine formulations increased the immune response to such vaccines. Freund reported use of water-in-oil (W/O) emulsions to enhance antibody response to an antigen. Addition of inactivated Mycobacteria to such emulsions (Freund's complete adjuvant or CFA) further enhances the cell-mediated response and may or may not enhance the humoral response.
The efficacy of vaccine adjuvants appears to be due to a sequestering or concentrating effect on an antigen or to stimulation of an inflammatory response or to both. CFA is not practical other than in laboratory experiments because local inflammation induced by its administration is unacceptably severe. Many other vaccine adjuvants have been employed in W/O as well as in oil-in-water (O/W) emulsions. Such adjuvants include muramyl dipeptide (MDP), inorganic aluminum compounds such as Al(OH).sub.3 and surfactants such as trehalose dimycolate (TDM), lipopolysaccharide (LPS)-lipid A, certain hydrophilic block polymers and many alkyl nitrogenous compounds which are highly lipophilic and water insoluble.
Useful surfactants have a small polar region attached to a large non-polar region; they interact at the interphase of hydrophilic and lipophilic surfaces in W/O and O/W emulsions. Because such surfactants typically cannot reduce the surface tension of immiscible liquids, i.e., oil and water, to form an emulsion, emulsifying agents are generally added. Commonly employed emulsifiers are the Tweens and the Spans.
Freund, Adv. Tuberc. Res. 7: 130 (1956), reviews use of water-oil emulsions as adjuvants.
Saponins, or sapogenin glycosides, are a type of glycosidic surfactant widely distributed in plants. Use of various saponin preparations as vaccine adjuvants, though not in W/O or O/W emulsions, is well-known.
Quil A is a saponin isolated from the bark of Quillaja saponaria Molina, a tree native to parts of South America. It consists of a carbohydrate moiety in glycoside linkage to the triterpenoid, quillaic acid. Its use as a vaccine adjuvant is well established. See, for example, Dalsgaard et al., Acta vet. Scand. 18: 349-360 (1977).
Bomford, Int. Arch. Allergy Appl. Immunol. 67(2): 127-131 (1982), reports use of cholesterol-saponin complexes as vaccine adjuvants. Bonati, U.S. Pat. No. 4,101,642, discloses use of saponin-sterol complexes, for example, aescin, Polygala saponins, tomatin or digitonin complexed with cholesterol, in pharmaceutical compositions.
Charlier et al., Arch. Exp. Vet.-Med. 27: 783 (1973), report studies with various saponin preparations.